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A case study of apparent immune activation following treatment of a colorectal cancer patient with an angiotensin receptor blocker Titmuss, Emma

Abstract

Despite being one of the most preventable cancers, colorectal cancer (CRC) affects a large proportion of the population and results in ~12% of all deaths due to cancer in Canada (Canadian Cancer Society, 2017). Standard treatments for CRC are chemotherapy based, but more targeted therapies are emerging as highly effective treatments across multiple disease types. The Personalised Oncogenomics (POG) program at BC Cancer aims to discover actionable genomic alterations using whole genome and transcriptome sequence analysis of incurable cancer patients (Laskin et al., 2015). Occasionally, selected patients may be offered a treatment predicted by the POG analysis. One particular metastatic CRC POG patient displayed a profound response upon treatment with an antihypertensive drug, irbesartan (Avapro), prescribed following genomic analysis of a biopsy sample that had revealed unusually high expression of FOS and JUN transcripts, downstream components of the pathway on which irbesartan acts. After a durable 18-month response to irbesartan, the patient relapsed and a second biopsy was taken, providing a unique opportunity to study the mechanisms underpinning the response and relapse of the patient. Gene set enrichment analysis of RNA and protein expression data revealed an increase in abundance of genes involved in immune system pathways following treatment with irbesartan, and results from multiplex immunohistochemistry panels indicated increased cytotoxic T cell infiltration following treatment. Combined with increases in protein and RNA abundance of negative immune checkpoints (often a resistance mechanism to immune activation), and a large repertoire of candidate neo-antigens, there is evidence to support the hypothesis that irbesartan stimulated an anti-tumour immune response. In contrast with immunotherapy agents such as immune checkpoint inhibitors (ICIs), irbesartan is substantially cheaper, and exhibits fewer side effects. If a biomarker of response to irbesartan can be identified, there may be future potential for this drug to be tested for clinical activity in a larger patient population. Furthermore, this case study demonstrates the utility of whole genome and transcriptome sequencing to study response and resistance to therapies and how these methods might be used to inform clinical decision making.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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